The long-term goal of this project is to formulate Innovative risk assessment methodologies on chemical mixtures by coupling physiologically based pharmacokinetics/pharmacodynamics (PB-PK/PD) and other experimental toxicology with statistical/mathematical modeling such as isobolographic analysis and response surface methodology. The central questions to ask are: (1) How should we handle chemical mixtures and toxicologic interactions?; (2) Can we develop "Predictive Toxicology" for chemical mixtures:/ (3) How may we incorporate state-of-the art science into the risk assessment process, particularly for chemical mixtures? To answer and to address these questions, we propose to use two approaches, the "Bottom- Up" and "Top-Down" approaches. The "Bottom-Up" approach refers to systematic toxicologic interaction studies starting with binary chemical mixtures based on toxic mechanism(s). A third, fourth,....chemical is then added based on mechanistic considerations and, in this way, we build up the chemical mixtures. In this project, for the "Bottom-Up" approach, we intend to study toxicologic interactions of Kepone and CCI based on the mechanistic concept that Kepone impaires tissue repair. The "Top-Down" approach, on the other hand, will start out with the chemical mixture of 4 groundwater contaminants (arsenic 1,2-dichloroeethane, trichloroethylene, and vinyl chloride. We will then systematically conduct toxicology experiments on organic and inorganic submixtures, component until we get to individual chemicals. Throughout these experiments, PB-PK/PD modeling coupled with isobolographic analysis and response surface methodology will be used to achieve the goal of "Predictive Toxicology."